Dermatological preparations

ABSTRACT

The present invention relates to a dermatologic preparation containing a diamide derivative represented by the following formula (1):  
                 
 
     (wherein, R 1  represents a linear or branched hydrocarbon group having 1 to 22 carbon atoms which may be substituted by one or more hydroxy and/or alkoxy groups, R 2  represents a linear or branched divalent hydrocarbon group having 1 to 12 carbon atoms, and R 3  represents a linear or branched divalent hydrocarbon group having 1 to 42 carbon atoms). This diamide derivative (1) is capable of fundamentally improving the water retention capacity and barrier functions of the horny layer, is excellent in miscibility and mixing stability and can be prepared efficiently at a low cost.

TECHNICAL FIELD

[0001] The present invention relates to dermatologic preparationscapable of exerting excellent effects of maintaining normal barrierfunctions of the horny layer, restoring and reinforcing damaged barrierfunctions, heightening water retention of the horny layer and remedyingskin chapping; and novel diamide derivatives having such effects.

BACKGROUND ART

[0002] When the water retention capacity or barrier functions of thehorny layer are weakened by some internal or external reasons, the skinsuffers from troubles such as chapping and acceleration of aging. It istherefore highly important to maintain and reinforce the water retentioncapacity and barrier functions of the horny layer for our healthy dailylife.

[0003] The present applicant has formerly proposed dermatologicpreparations comprising an amide derivative represented by the followingformula (3):

[0004] (wherein, R^(a) represents a linear or branched, saturated orunsaturated hydrocarbon group having 10 to 40 carbon atoms, R^(b)represents a linear or branched divalent hydrocarbon group having 3 to39 carbon atoms, R^(c) represents a hydrogen atom, a linear or branched,saturated or unsaturated hydrocarbon group having 10 to 40 carbon atomsor an acyl group) as a dermatologic preparation capable of essentiallyimproving (maintaining, reinforcing) the barrier functions of the hornylayer (Japanese Patent Application Laid-Open (Kokai) No. 4-128256).

[0005] Although these amide derivatives exert the above-describedexcellent effects, they still involve some problems in miscibility ormixing stability because they do not always have sufficient solubilityin bases and solution stability. Moreover, preparation of such amidederivatives requires multi-stage reaction, inevitably causing anincrease in their production cost.

[0006] An object of the present invention is therefore to provide acompound capable of essentially improving the water retention capacityand barrier functions of the horny layer, having improved miscibility ormixing stability, and being available efficiently at a low cost; and adermatologic preparation which contains the above-described compoundand, by maintaining and reinforcing the water retention capacity andbarrier functions of the horny layer, exerts effects of preventing orremedying skin troubles such as chapping, protecting the hair with itspenetrated component, improving touch feel of the hair and preventing orremedying chapping of the scalp.

DISCLOSURE OF THE INVENTION

[0007] The present invention provides a dermatologic preparation,humectant or skin-barrier-function reinforcing agent, which comprises adiamide derivative represented by the following formula (1):

[0008] (wherein R¹ represents a linear or branched hydrocarbon grouphaving 1 to 22 carbon atoms which may be substituted by one or morehydroxy and/or alkoxy groups, R² represents a linear or brancheddivalent hydrocarbon group having 1 to 12 carbon atoms, and R³represents a linear or branched divalent hydrocarbon group having 1 to42 carbon atoms).

[0009] The present invention also provides a diamide derivativerepresented by the following formula (2):

[0010] (wherein, R¹ represents a linear or branched hydrocarbon grouphaving 1 to 22 carbon atoms which may be substituted by one or morehydroxy and/or alkoxy groups, R² represents a linear or brancheddivalent hydrocarbon group having 1 to 12 carbon atoms, and R^(3a)represents an alkylene group or an alkenylene group having 1 to 4 doublebonds, which alkylene or alkenylene group may be linear or branched andhas 11 to 42 carbon atoms)

BEST MODE FOR CARRYING OUT THE INVENTION

[0011] In the diamide derivatives (1) and (2), preferred as R¹ arelinear or branched C₁₋₂₂ alkyl groups which may have 1 to 3 substituentsselected from a hydroxy group and C₁₋₆ alkoxy groups. Of these, C₁₋₁₈alkyl groups, C₁₋₁₈ mono- or di-hydroxyalkyl groups, (C₁₋₆alkoxy-substituted)-(C₁₋₁₈ alkyl) groups, and (hydroxy- and C₁₋₆alkoxy-substituted)-(C₁₋₁₈ alkyl) groups are preferred, of which C₁₋₁₈alkyl groups, C₂₋₁₂ mono- or di-hydroxyalkyl groups, (C₁₋₆alkoxy-substituted)-(C₂₋₁₂ alkyl) groups, and (hydroxy- and C₁₋₆alkoxy-substituted)-(C₂₋₁₂ alkyl) groups are more preferred. Specificexamples include methyl, ethyl, propyl, butyl, hexyl, dodecyl,2-methylpropyl, 2-ethylhexyl, methyl-branched isostearyl,2-hydroxyethyl, 9-hydroxynonyl, 2,3-dihydroxypropyl, 2-methoxyethyl,2-hydroxy-3-methoxypropyl and 9-methoxynonyl groups. Of these,2-hydroxyethyl, methyl, dodecyl and 2-methoxyethyl groups are morepreferred.

[0012] As R², linear or branched C₁₋₁₂ alkylene groups are preferred,with linear or branched C₂₋₆ alkylene groups being more preferred.Specific examples include ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, methylmethylene (ethylidene),1-methylethylene, 2-methylethylene, 1-methyltrimethylene,0.2-methyltrimethylene, 1,1-dimethylethylene and 2-ethyltrimethylenegroups, of which ethylene and trimethylene groups are more preferred.

[0013] In the formula (1), linear or branched divalent hydrocarbongroups having 2 to 34 carbon atoms are preferred as R³, with alkylenegroups and alkenylene groups having 1 to 4 double bonds each of whichmay be linear or branched and has 2 to 34 carbon atoms, particularly,alkylene groups and alkenylene groups having 1 to 4 double bonds each ofwhich may be linear or branched and has 2 to 24 carbon atoms beingpreferred. Specific examples include ethylene, trimethylene,tetramethylene, hexamethylene, heptamethylene, octamethylene,decamethylene, undecamethylene, dodecamethylene, tridecamethylene,tetradecamethylene, hexadecamethylene, octadecamethylene,tricosamethylene, hexacosamethylene, triacontamethylene,1-methylethylene, 2-ethyltrimethylene, 1-methylheptamethylene,2-methylheptamethylene, 1-butylhexamethylene,2-methyl-5-ethylheptamethylene, 2,3,6-trimethylheptamethylene,6-ethyldecamethylene, 7-methyltetradecamethylene,7-ethylhexadecamethylene, 7,12-dimethyloctadecamethylene,8,11-dimethyloctadecamethylene, 7,10-dimethyl-7-ethylhexadecamethylene,1-octadecylethylene, 9,10-dioctyloctadecamethylene,8,9-dinonylhexadecamethylene, ethenylene, 1-octadecenylethylene,7,11-octadecadienylene, 7-ethenyl-9-hexadecamethylene,7,12-dimethyl-7,11-octadecadienylene,8,11-dimethyl-7,11-octadecadienylene,9,10-dioctyl-7,11-octadecadienylene and8,9-dinonyl-6,10-hexadecadienylene groups. Of these,7,12-dimethyloctadecamethylene, 7,12-dimethyl-7,11-octadecadienylene,octadecamethylene, octamethylene, decamethylene, undecamethylene andtridecamethylene groups are more preferred.

[0014] In the formula (2), preferred as R^(3a) are alkylene groups andalkenylene groups having 1 to 4 double bonds each of which may be linearor branched and has 12 to 34 carbon atoms, with alkylene groups andalkenylene groups having 1 to 4 double bonds each of which may be linearor branched and has 12 to 24 carbon atoms being more preferred. Ofthese, 7,12-dimethyloctadecamethylene,7,12-dimethyl-7,11-octadecadienylene, octadecamethylene andtridecamethylene groups are still more preferred.

[0015] In the diamide derivatives (2) of the present invention,particularly preferred are compounds of the formula (2) having, as R¹,R² and R^(3a), the groups within the above-described more preferredranges in combination, respectively. In the diamide derivatives (1) tobe used for the dermatologic preparations of the present invention,particularly preferred are compounds of the formula (1) having, as R¹,R² and R³, groups within the above-described more preferred ranges incombination, respectively.

[0016] Particularly preferred examples of the diamide derivatives (1) tobe used for the dermatologic preparations of the present inventioninclude:

[0017] Particularly preferred examples of the diamide derivatives (2) ofthe present invention include the above-exemplified compounds (A) to(C), (F) to (J) and (L).

[0018] The diamide derivatives (1) to be used for the dermatologicpreparations of the present invention can be prepared by a known amidesynthesis method. A preparation process, for example, in accordance withthe following reaction scheme can efficiently yield them at a low cost.

[0019] (wherein, R¹, R² and R³ have the same meanings as describedabove).

[0020] The target diamide derivative (1) is available efficiently bycondensing a corresponding carboxylic acid (4) or reactive derivativethereof (ester, acid halide or acid anhydride) with an amine (5). Thiscondensation is preferably conducted in the presence or absence of adehydrating agent such as dicyclohexylcarbodiimide, or a base, forexample, an alkali metal hydroxide such as potassium hydroxide or sodiumhydroxide, an alkaline earth metal hydroxide such as calcium hydroxide,an alkali metal carbonate such as potassium carbonate, an alkali earthmetal carbonate such as calcium carbonate, an alkali metal alcoholatesuch as sodium methoxide, sodium ethoxide or potassium-tert-butoxide ora tertiary amine such triethylamine or pyridine under a pressure rangingfrom normal pressure to reduced pressure at 1.3 Pa at room temperatureto 250° C. Upon condensation, the amine (5) is preferably used in anexcess amount, more specifically, 2 equivalents or greater of thedicarboxylic acid (4) or reactive derivative thereof. For rapid progressof the reaction, it is preferred to conduct the reaction while removing,out of the system, water or an alcohol generated by the reaction. Thediamide derivative (1) thus available can be purified in a known mannersuch as washing with water, column chromatography, distillation,crystallization, recrystallization or powder treatment. Since thediamide derivative (1) obtained in such a manner has effects ofpenetrating into the lipid layer of the horny layer, thereby maintainingand improving the water retention capacity and barrier functions of thehorny layer, it is useful as a humectant or skin-barrier-functionreinforcing agent.

[0021] The dermatologic preparations of the present invention areobtained by incorporating the amide derivative (1) in a base (carrier)ordinarily employed for dermatologic preparations. They can be preparedby mixing necessary raw materials in a known manner.

[0022] The dermatologic preparations of the present invention may bebroadly classified into medicinal dermatologic preparations andcosmetics depending on the applications thereof. Examples of themedicinal dermatologic preparations include various ointments containingpharmaceutically effective ingredients. These ointments may containeither an oily base or an O/W or W/O emulsion base. No particularlimitation is imposed on the oily base and examples thereof includevegetable oils, animal oils, synthetic oils, fatty acids and natural andsynthetic glycerides. No particular limitation is imposed on thepharmaceutically effective ingredients and examples thereof includeanalgesic antiinflammatory agents, antipruritic agents, bactericides,astringents, skin emollients and hormones as needed.

[0023] When the dermatologic preparations of the present invention areused as cosmetics (including skin cosmetics and hair cosmetics), theessential ingredient, that is, the diamide derivative (1), may bearbitrarily blended with commonly used oleaginous components,surfactants, humectants, ultraviolet absorbers, whitening agents,anti-wrinkle compositions, alcohols, chelating agents, pH regulators,antiseptics, thickeners, colorants and 0.10 perfumes.

[0024] These cosmetics may be formulated into various forms such as W/Oand O/W emulsion cosmetics, cream, cosmetic milky lotion, cosmeticlotion, oily cosmetic, lipstick, foundation, bath agent, skin cleanser,nail treatment and hair cosmetics. No particular limitation is imposedon the hair cosmetics and examples include hair tonic, hair dressing,hair rinse, hair treatment, hair conditioner, hair styling agent,shampoo, hair nourishment and hair growth stimulant.

[0025] Although there is no particular limitation imposed on the contentof the diamide derivative (1) in the dermatologic preparation of thepresent invention. In the case of an emulsion type dermatologicpreparation, 0.001 to 50 wt. % (which will hereinafter be described %simply) based on the whole composition is preferred. In the case of anoily dermatologic preparation containing a liquid hydrocarbon such assqualane as a base, 0.01 to 50% based on the whole composition ispreferred. In either case, 0.01 to 20% is particularly preferred.Particularly, for prevention or remedy of chapping, addition of 0.1 to20% is preferred. Use of the dermatologic preparation as skin cosmeticsis particularly preferred.

[0026] When the dermatologic preparations of the present invention serveas a medicinal dermatologic preparation or skin cosmetic, surfactantssuch as nonionic surfactants, anionic surfactants, cationic surfactantsand amphoteric surfactants may be incorporated. Of these, nonionicsurfactants such as polyoxyethylene alkyl ethers, polyoxyethylene fattyacid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fattyacid esters, fatty acid monoglycerides and glyceryl ethers arepreferred. As its content, 0.01 to 20%, particularly 0.1 to 10% in thewhole preparation is preferred.

[0027] Although no particular limitation is imposed on the content ofthe diamide derivative (1) in the hair cosmetic of the presentinvention, preferred is 0.001 to 5% for shampoo, 0.1 to 20% for rinse,treatment, conditioner or styling agent and 0.01 to 5% for hair liquidor hair tonic.

[0028] The hair cosmetic of the present invention may containsurfactants such as anionic surfactants, cationic surfactants, nonionicsurfactants and amphoteric surfactants and in addition, componentsordinarily employed for hair cosmetics. When the hair cosmetic of thepresent invention is a shampoo, it may contain, as a main active agent,an anionic surfactant such as an alkyl ether sulfate, alkyl sulfate orolefin sulfonate. As its content, 5 to 30%, particularly 10 to 20%, eachbased on the whole composition, is preferred.

[0029] When the cosmetic of the present invention is a hair rinse,conditioner, hair treatment or hair styling agent, it may contain acationic surfactant such as mono- or di-(long chain alkyl) tetraammoniumsalt, a nonionic surfactant such as polyoxyethylene alkyl or alkenylether or an oil/fat such as liquid paraffin for imparting the hair withgood touch feel. The content of the cationic or nonionic surfactant ispreferably 0.1 to 50%, particularly 0.5 to 20% in the whole composition.

[0030] When the hair cosmetic is a hair liquid or hair tonic, it maycontain a nonionic surfactant such as polyoxyethylene. The nonionicsurfactant is preferably added in an amount of 0.01 to 20%, particularly0.1 to 5% in the whole composition.

[0031] The skin cosmetic or hair cosmetic of the present inventioncontaining the diamide derivative (1) may be formulated into an aqueoussolution, ethanol solution, emulsion, suspension, gel, solid, aerosol orpowder without any limitation.

EXAMPLES Preparation Example 1

[0032] Preparation of Compound (A)

[0033] In a flask equipped with a stirrer, a nitrogen inlet tube and adistilling tube, 150 g of dimethyl 8,13-dimethyl-eicosanedioate(“IPS-22M”, product of Okamura Seiyu), 159 g of diglycolamine and 7.5 gof sodium methoxide were charged. The mixture was stirred for 5 hours at140° C. under reduced pressure (20 torr), while distilling off themethanol by-produced. After completion of the reaction, excessdiglycolamine was distilled off under reduced pressure. The residue wasthen washed with water, whereby 200 g (yield: 98%) of the title compoundwas obtained. The resulting compound 1 (A) has following physicalproperties:

[0034] Colorless Paste

[0035]¹H-NMR (CDCl₃, δ): 0.67-0.91(m,6H), 0.93-1.58(m,26H),1.59-1.76(m,4H), 2.17(t,J=7.2 Hz,4H), 2.72-3.12(m,2H), 3.33-3.52(m,4H),3.52-3.64(m,8H), 3.65-3.85(m,4H), 6.13-6.56(m,2H).

Preparation Examples 2 to 15

[0036] In a similar manner to Example 1 except for the use of thedicarboxylic acid (4) or reactive derivative thereof and, as the amine(5), the compound shown in Table 1 or 2, Compounds (B) to (O) wereobtained. These raw materials are shown in Tables 1 and 2, together withthe physical properties of the diamide derivatives. TABLE 1 DiamideDicarboxylic acid (4) derivative (1) or reactive prepared derivativethereof Amine (5) Physical properties Prep. Compound Dimethyl 7,12-Diglycolamine Colorless paste Ex. 2 (B) dimethyl-7,11- ¹H-NMR(CDCl₃, δ):1.05-1.45(m, 16H), 1.45-1.72 octadecadiene- (m, 8H), 1.79-2.08(m, 6H),2.14 1,18-dicarboxylate (t, J=7.8Hz, 4H), 2.83-3.15 (m, 2H), 3.32-3.47(“IPU-22MM”, (m, 4H), 3.47-3.61(m, 8H), 3.61-3.78(m, 4H), product ofOkamura 4.52-5.19(m, 2H), 6.26-6.58(m, 2H). Seiyu) Prep. CompoundDimethyleicosanedioate Diglycolamine White crystals, Melting point: 135°C. Ex. 3 (C) (“SL-20MM”, ¹H-NMR(MeOH-d₄, δ): 1.18-1.44(m, 28H),1.48-1.71 product of Okamura (m, 4H), 2.18(t, J=7.4Hz, 4H), 3.31-3.43Seiyu) (m, 4H), 3.46-3.60(m, 8H), 3.60-3.71(m, 4H), 4.49-4.68(m, 2H).Prep. Compound Dimethyl sebacate Diglycolamine White solid, Meltingpoint: 107° C. Ex. 4 (D) ¹H-NMR(CDCl₃, δ): 1.22-1.40(m, 8H), 1.54-1.72(m, 4H), 2.19(t, J=7.2Hz, 4H), 2.70-2.90 (m, 2H), 3.36-3.54(m, 4H),3.54-3.70(m, 8H), 3.70-3.89(m, 4H), 6.13-6.30(m, 2H). Prep. CompoundDimethyl succinate Diglycolamine White crystals, Melting point: 85° C.Ex. 5 (E) ¹H-NMR(CDCl₃, δ): 2.52(s, 4H), 3.30-3.50 (m, 4H), 3.50-3.64(m,8H), 3.64-3.88(m, 4H), 7.12-7.33(m, 2H). Prep. Compound Dimethyl 8,13-3-Methoxy- Colorless paste Ex. 6 (F) dimethyleicosanedioate propylamine¹H-NMR(CDCl₃, δ): 0.67-0.95(m, 6H), 1.00-1.48 (“IPS-22MM”, (m, 26H),1.48-1.70(m, 4H), 1.70-1.88(m, 4H), product of Okamura 2.14(t, J=7.2Hz,4H), 3.23-3.41(m, 10H), 3.41-3.58 Seiyu) (m, 4H), 5.96-6.20(m, 2H).Prep. Compound Dimethyl 8,13- 3- White crystals, Melting point: 36° C.Ex. 7 (G) dimethyleicosanedioate Dodecyloxy- ¹H-NMR(CDCl₃, δ):0.64-0.98(m, 12H), 0.98-1.46 (“IPS-22MM”, propylamine (m, 62H),1.46-1.70(m, 8H), 1.70-1.88 product of Okamura (m, 4H), 2.14(t, J=7.2Hz,4H), 3.26-3.47(m, 8H), Seiyu) 3.47-3.61(m, 4H), 6.09-6.34(m, 2H). Prep.Compound Dimethyl 8,13- 2-(2-Methoxy- Colorless paste Ex. 8 (H)dimethyleicosanedioate ethoxy)- ¹H-NMR(CDCl₃, δ): 0.69-0.88(m, 6H),0.93-1.41 (“IPS-22MM”, ethylamine (m, 26H), 1.49-1.68(m, 4H), product ofOkamura 2.27(t, J=7.2Hz, 4H), 3.36(s, 6H), 3.40-3.68 Seiyu) (m, 16H),5.88-6.06(m, 2H).

[0037] TABLE 2 Diamide Dicarboxylic acid (4) derivative (1) or reactiveprepared derivative thereof Amine (5) Physical properties Prep. Compound(I) Dimethyl Diglycolamine White crystals, Melting point: 127° C. Ex. 9pentadecanedioate ¹H-NMR(MeOH-d₄, δ): 1.20-1.45(m, 18H), 1.45-1.75 (m,4H), 2.18(t, J=7.4Hz, 4H), 3.25-3.45 (m, 8H), 3.52(t, J=5H.1Hz, 4H),3.60-3.75(m, 4H), 4.60-4.70(m, 2H). Prep. Compound Dimethyl brassylateDiglycolamine White crystals, Melting point: 120° C. Ex. 10 (J)¹H-NMR(MeOH-d₄, δ): 1.20-1.45(m, 14H), 1.50-1.70 (m, 4H), 2.18(t,J=7.4Hz, 4H), 3.25-3.45 (m, 8H), 3.52(t, J=5.0Hz, 4H), 3.60-3.75(m, 4H),4.60-4.70(m, 2H). Prep. Compound Dimethyl Diglycolamine White solid,Melting point: 118° C. Ex. 11 (K) dodecanedioate ¹H-NMR(MeOH-d₄, δ):1.20-1.45(m, 12H), 1.45-1.75 (m, 4H), 2.18(t, J=7.4 Hz, 4H), 3.25-3.45(m, 8H), 3.52(t, J=5.1Hz, 4H), 3.60-3.75(m, 4H), 4.60-4.70(m, 2H). Prep.Compound Dimethyl 3-Methoxy- White crystals, Melting point: 134° C. Ex.12 (L) Eicosanedioate propylamine ¹H-NMR(CDCl₃, δ): 1.15-1.40(m, 32H),1.52-1.70 (m, 4H), 1.77(quintet, J=6.1Hz, 4H), 2.15 (t, J=7.6Hz, 4H),3.30-3.43(m, 4H), 3.35(s, 6H), 3.48(t, J=5.7Hz, 4H), 5.90-6.10(m, 2H).Prep. Compound Dimethyl 3-Methoxy- White crystals, Melting point: 129°C. Ex. 13 (M) dodecanedioate propylamine ¹H-NMR(CDCl₃, δ): 1.15-1.40(m,12H), 1.50-1.70 (m, 4H), 1.70-1.90(m, 4H), 2.15 (t, J=6.1Hz, 4H),3.30-3.45(m, 4H), 3.35(s, 6H), 3.48(t, J=5.8Hz, 4H), 5.95-6.05(m, 2H).Prep. Compound Dimethyl sebacate 3-Methoxy- White crystals, Meltingpoint: 125° C. Ex. 14 (N) propylamine ¹H-NMR(CDCl₃, δ): 1.20-1.45(m,8H), 1.50-1.70 (m, 4H), 1.71-1.90(m, 4H), 2.15(t, J=7.5Hz, 4H),3.25-3.45(m, 4H), 3.35(s, 6H), 3.48 (t, J=5.8Hz, 4H), 6.00-6.20(m, 2H).Prep. Compound Dimethyl sebacate 3- White crystals, Melting point: 134°C. Ex. 15 (O) Dodecyloxy- ¹H-NMR(CDCl₃, δ): 0.80-1.00(m, 6H), 1.15-1.45propylamine (m, 44H), 1.45-1.70(m, 8H), 1.76(quintet, J=6.1Hz, 4H),2.13(t, J=7.6Hz, 4H), 3.30-3.48 (m, 8H) 3.52(t, J=5.7Hz, 4H),6.05-6.25(m, 2H)

Preparation Example 16

[0038] In a flask equipped with a stirrer, a nitrogen inlet tube and adistilling tube, 537 g of 8,13-dimethyleicosanedioic acid (“IPS-22”,product of Okamura Seiyu) was charged, followed by dropwise addition of381 g of diglycolamine over 4 hours under stirring at 180° C. in anitrogen gas stream. After saturation for 4 hours under the sameconditions, saturation was conducted for further 4 hours at 200° C. Theabove-described dropwise addition and saturation were conducted in anitrogen gas stream while distilling off water by-produced. Aftercompletion of the reaction, excess diglycolamine was removed bydistillation under reduced pressure and steaming. In a moleculardistillation apparatus, a low-boiling-point substance was removed underthe conditions of 200° C. and 0.7 Pa, whereby 680 g (yield: 86%) of thecrude Compound (A) was obtained as a pale yellow paste. Mainly forbleaching, 20 g of the compound was dissolved in 20.0 g of ethanol and0.40 g of activated charcoal was added to the resulting solution,followed by stirring at 80° C. for 2 hours. The activated charcoal wasfiltered out and the residue was concentrated under reduced pressure,whereby 19.9 g of Compound (A) was obtained as a colorless paste.

Preparation Example 17

[0039] In a flask equipped with a stirrer, a nitrogen inlet tube and adistilling tube, 770 g of sebacic acid was charged, followed by dropwiseaddition of 1001 g of diglycolamine over 4 hours under stirring at 200°C. in a nitrogen gas stream. The reaction mixture was saturated for 5hours under the same conditions. The above-described dropwise additionand saturation were conducted in a nitrogen gas stream while distillingoff water by-produced. After completion of the reaction, excessdiglycolamine was removed by distillation under reduced pressure andsteaming, whereby 1410 g (yield: 98%) of the crude Compound (D) wasobtained as white crystals. The crystals were re-crystallized from 4510g of a 6.25% aqueous solution of sodium sulfate, whereby 1085 g (yield:76%) of Compound (D) was obtained as white crystals.

Preparation Example 18

[0040] In a flask equipped with a stirrer, a nitrogen inlet tube and adistilling tube, 100 g of 8,13-dimethyleicosanedioic acid (“IPS-22”,product of Okamura Seiyu) was charged, followed by the dropwise additionof 61 g of 3-methoxypropylamine over 3 hours at 180° C. under stirringin a nitrogen gas stream. After saturation for 3 hours under the sameconditions, saturation was conducted for further 5 hours at 200° C. Theabove-described dropwise addition and saturation were conducted under anitrogen gas stream while distilling off water by-produced. Aftercompletion of the reaction, excess 3-methoxypropylamine was removed bydistillation under reduced pressure and steaming, whereby 137 g (yield:99%) of the crude Compound (F) was obtained as a pale yellow paste. Thecrude Compound (F) was distilled (at 220° C. and 0.7 to 0.3 Pa), whereby106 g (yield: 77%) of Compound (F) was obtained as a colorless paste.

[0041] Test 1

[0042] Dermatologic preparations (invention products) composed of 33% ofeach of the diamide derivatives prepared in Preparation Examples 1 to 18and 67% of vaseline were prepared. Their effects on skin conductance andchapping were evaluated in the below-described manner. For comparison, adermatologic preparation (Comparative Product 1) composed of vaselinealone was evaluated in the same manner. Table 3 shows the results.

[0043] (Test Method)

[0044] Ten female subjects aged 20 to 50 years, who suffered chapping incheeks in winter, were employed. Different dermatologic preparationswere applied on the right and left cheeks of the subjects for 2 weeks,respectively. On the next day after completion of the application for 2weeks, the following items were examined.

[0045] (1) Skin Conductance

[0046] The face of each subject was washed with warm water of 37° C.After she was allowed to stand in a room at 20° C. under a humidity of45% for 20 minutes, the water content of the horny layer was measuredusing a skin conductance meter (product of IBS Co., Ltd.).

[0047] (2) Skin Chapping Score

[0048] Skin chapping was observed with naked eyes and evaluated based onthe following criteria. Each score is expressed in the mean value.

[0049] 0: No chapping is observed.

[0050] 1: Slight chapping is observed.

[0051] 2: Chapping is observed.

[0052] 3: Somewhat serious chapping is observed.

[0053] 4: Serious chapping is observed. TABLE 3 Dermatologic DiamideSkin Skin chapping preparation derivative conductance score Inventionproduct 1 Compound (A) 28 0.6 Invention product 2 Compound (B) 25 0.9Invention product 3 Compound (C) 21 1.0 Invention product 4 Compound (D)30 0.5 Invention product 5 Compound (E) 18 1.0 Invention product 6Compound (F) 20 1.2 Invention product 7 Compound (G) 17 1.1 Inventionproduct 8 Compound (H) 19 1.3 Invention product 9 Compound (J) 23 0.8Invention product 10 Compound (L) 19 1.3 Invention product 11 Compound(N) 18 1.5 Comparative product 1 — 5 2.7 (vaseline alone)

[0054] The results show that the invention products 1 to 11 weresuperior to the comparative product in effects of increasing the watercontent of the horny layer and remedying skin chapping.

[0055] Test 2

[0056] Dermatologic preparations (invention products) of the presentinvention composed of 10% of each of the diamide derivatives prepared inPreparation Examples 1 to 18 and 90% of squalane were prepared and theirtransepidermal water loss and percutaneous absorption were evaluated bythe below-described test method. For comparison, a dermatologicpreparation (Comparative Product 2) composed of squalane alone was alsoevaluated by the test. Table 4 shows the results.

[0057] (Test Method)

[0058] Wistar male rats were fed with a feed free from essential fattyacids and the resulting rats with essential fatty acid deficiency wereemployed in this test. The dorsal part of the rat showing essentialfatty acid deficiency was carefully shaven and each dermatologicpreparation to be evaluated was applied thereto once a day for 2 weeks.A group consisting of 5 rats was provided for the test of eachdermatologic preparation. After 2 weeks, the following items wereexamined.

[0059] (1) Transepidermal Water Loss

[0060] The dorsal part of the test rat was washed with warm water andthe animal was the allowed to stand in a room (at 23° C. under ahumidity of 45%) for 1 hour. The transepidermal water loss was thenmeasured with an evaporimeter. Each measured value is expressed in meanvalue.

[0061] (2) Percutaneous Water Absorption

[0062] After the dorsal skin of the rat was washed with warm water of37° C., it was cut and fixed in a percutaneous absorption chamber withthe epidermal side thereof directed upward. A lower receiver of thechamber was filled with a phosphate buffer solution while a container onthe epidermal side thereof was charged with 1 ml of a phosphate buffersolution containing 37 KBq of ¹⁴C-salicylic acid. Two hours after theywere allowed to stand, 1 mL of the phosphate buffer solution was takenout of the lower receiver and the radioactivity of the ¹⁴C-salicylicacid which had penetrated into it was measured. Each value is expressedin mean value. TABLE 4 Dermatologic Diamide Transepidermal Percutaneouspreparation derivative water loss absorption Invention product 12Compound (A) 12 572 Invention product 13 Compound (B) 12 558 Inventionproduct 14 Compound (C) 21 1685 Invention product 15 Compound (D) 15 997Invention product 16 Compound (E) 25 1772 Invention product 17 Compound(F) 20 1487 Invention product 18 Compound (G) 16 1096 Invention product19 Compound (H) 23 2036 Invention product 20 Compound (I) 18 1197Invention product 21 Compound (J) 21 1490 Invention product 22 Compound(K) 22 1694 Invention Product 23 Compound (L) 15 705 Invention Product24 Compound (M) 25 2038 Invention Product 25 Compound (N) 23 1560Invention Product 26 Compound (O) 27 2476 Comparative product 2 — 312994 (squalane alone)

[0063] The results show that the invention products 12 to 26 weresuperior to the comparative product 2 in effects of suppressingtransepidermal water loss and percutaneous absorption and remedyingchapping.

[0064] Test 3

[0065] Hair rinses having the compositions as listed in Table 5 wereprepared and excessive dryness and touch feel of the hair after treatedwith the resulting hair rinses were evaluated by a panel of 5 experts inaccordance with the below-described criteria. The results are shown inTable 6.

[0066] (Evaluation Criteria)

[0067] −2: Bad

[0068] −1: slightly bad

[0069] 0: neither good nor bad

[0070] +1: Slightly good

[0071] +2: Good TABLE 5 Invention Invention Invention ComparativeComposition (%) product 27 Product 28 Product 29 Product 3 Distearyldimethyl 2 2 2 2 ammonium chloride Propylene glycol 3 3 3 3 Compound (A)1 — — — Compound (D) — 1 — — Compound (F) — — 1 — Water Balance BalanceBalance Balance

[0072] TABLE 6 Invention Invention Invention Comparative Evaluationitems product 27 product 28 product 29 Product 3 Excessive dryness +1.4+1.2 +1.6 −0.4 of the hair Favorable touch feel +1.2 +1.6 +1.8 −0.5

[0073] Apparent from the above-described table, the invention products27 to 29 are superior to the comparative product 3 in the effects ofalleviating excessive hair dryness and improving the touch feel of thehair.

Example 1

[0074] A skin lotion having the composition as shown in Table 7 wasprepared in a conventional manner. The resulting hair lotion exhibitedexcellent effects of preventing or remedying chapping. Compound (A) andCompound (F) were excellent in miscibility and mixing stability. TABLE 7(Composition) (%) Compound (A) or Compound (F) 1 Glycerin monostearate 1Ethanol 15 Propylene glycol 4 Isopropyl palmitate 3 Lanolin 1 Methylparaoxybenzoate 0.1 Ceramide 1 Perfume Trace Colorant Trace WaterBalance

Example 2

[0075] An O/W cream having the composition as shown in Table 8 wasprepared in a conventional manner. The resulting O/W cream exhibitedexcellent effects of preventing or remedying chapping. Compound (D) andCompound (F) were excellent in miscibility and mixing stability. TABLE 8(Composition) (%) Compound (D) or Compound (F) 3.5 Squalane 2.0Neopentyl glycol dicaprate 3.0 Polyoxyethylene (20) sorbitanmonostearate 2.1 Sorbitan monostearate 0.9 Polyoxyethylene hardenedcastor oil 1.0 (“EMANON CH-40”, product of Kao Corp.) Monoisostearylglyceryl ether 0.2 86% glycerin 5.0 Methyl paraben 0.3 Water Balance

Example 3

[0076] A shampoo having the composition as shown in Table 9 was preparedin a conventional manner. This shampoo improved the touch feel of thehair and prevented remedied the chapping of the scalp. Compound (F) andCompound (A) were excellent in miscibility and mixing stability. TABLE 9(Composition) (%) Polyoxyethylene (25) lauryl ether sulfate 15 Sodiumsalt Coconut oil fatty acid diethanol amide 3 Compound (A) or Compound(F) 2 Perfume 0.5 Colorant Trace Citric acid Trace Water Balance

Example 4

[0077] A hair liquid composition having the composition as shown inTable 10 was prepared in a conventional manner. The resulting hairliquid composition imparted the hair with excellent style retention andmanageability and good touch feel. Compound (D) and Compound (F) wereexcellent in miscibility and mixing stability. TABLE 10 (Composition)(%) Compound (D) or Compound (F) 1 Polyoxypropylene (30) butyl ether15.0 Ethanol 40.0 Water Balance Perfume 0.3

INDUSTRIAL APPLICABILITY

[0078] Diamide derivatives (I) penetrate the lipid layer between hornycells, thereby exerting effects of improving (maintaining•reinforcing)water retention capacity and barrier functions of the horny layer; andby these effects, they prevent or remedy the skin chapping and preventaging of the skin. When they are applied to the hair, they penetrateinto the hair, thereby heightening their protective effects, improvingthe touch feel of the hair and preventing or remedying the chapping ofthe scalp. In addition, they have good solubility and stability in abase and have excellent mixing stability, making it possible to preparea dermatological preparation efficiently at a low cost.

1. A dermatologic preparation, which comprises a diamide derivativerepresented by the following formula (1):

(wherein, R¹ represents a linear or branched hydrocarbon group having 1to 22 carbon atoms which may be substituted by one or more hydroxyand/or alkoxy groups, R² represents a linear or branched divalenthydrocarbon group having 1 to 12 carbon atoms, and R³ represents alinear or branched divalent hydrocarbon group having 1 to 42 carbonatoms).
 2. A dermatologic preparation according to claim 1, which is acosmetic preparation.
 3. A dermatologic preparation as claimed in claim1 or 2, wherein R¹ represents a linear or branched alkyl group having 1to 22 carbon atoms which may have 1 to 3 substituents selected from ahydroxy group and C₁₋₆ alkoxy groups, R² represents a linear or branchedhydrocarbon group having 1 to 12 carbon atoms, and R³ represents analkylene group or an alkenylene group having 1 to 4 double bonds, whichalkylene or alkenylene group may be linear or branched and has 2 to 34carbon atoms.
 4. A humectant comprising, as an effective ingredient, adiamide derivative represented by the following formula (1):

(wherein, R¹ represents a linear or branched hydrocarbon group having 1to 22 carbon atoms which may be substituted by one or more hydroxyand/or alkoxy groups, R² represents a linear or branched divalenthydrocarbon group having 1 to 12 carbon atoms, and R³ represents alinear or branched divalent hydrocarbon group having 1 to 42 carbonatoms).
 5. A skin barrier function reinforcing agent comprising, as aneffective ingredient, a diamide derivative represented by the followingformula (1):

(wherein, R¹ represents a linear or branched hydrocarbon group having 1to 22 carbon atoms which may be substituted by one or more hydroxyand/or alkoxy groups, R² represents a linear or branched divalenthydrocarbon group having 1 to 12 carbon atoms, and R³ represents alinear or branched divalent hydrocarbon group having 1 to 42 carbonatoms).
 6. A diamide derivative represented by the following formula(2):

(wherein, R¹ represents a linear or branched hydrocarbon group having 1to 22 carbon atoms which may be substituted by one or more hydroxyand/or alkoxy groups, R² represents a linear or branched divalenthydrocarbon group having 1 to 12 carbon atoms, and R^(3a) represents analkylene group or an alkenylene group having 1 to 4 double bonds, whichalkylene or alkenylene group may be linear or branched and has 11 to 42carbon atoms).
 7. A diamide derivative according to claim 6, wherein R¹represents a linear or branched alkyl group having 1 to 22 carbon atomswhich may have 1 to 3 substituents selected from a hydroxy group andC₁₋₆ alkoxy groups, R² represents a linear or branched alkylene grouphaving 1 to 12 carbon atoms, and R^(3a) represents an alkylene group oran alkenylene group having 1 to 4 double bonds, which alkylene oralkenylene group may be linear or branched and has 12 to 34 carbonatoms.